MAN2C1-congenital disorder of deglycosylation 2

Mendelian MONDO:0030770 Pathograph 4 Show in embeddings browser congenital disorder of deglycosylation

MAN2C1-congenital disorder of deglycosylation 2 is an autosomal recessive free-oligosaccharide catabolism disorder caused by biallelic MAN2C1 variants. MAN2C1 encodes a cytosolic alpha-mannosidase that trims free oligosaccharides generated during N-glycosylation and glycoprotein degradation. Pathogenic variants cause accumulation and delayed processing of free oligosaccharides in patient-derived cells, producing a neurodevelopmental disorder with dysmorphic features, congenital anomalies including tongue hamartoma, intellectual disability, and brain anomalies such as polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of the brainstem and cerebellar vermis.

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1
Inheritance
3
Pathophys.
3
Phenotypes
1
Gaps
4
Pathograph
1
Genes
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
other glycan metabolism
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported individuals have biallelic pathogenic MAN2C1 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1"
The initial cohort establishes biallelic MAN2C1 variants in affected individuals.
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Discussions and Knowledge Gaps

1
Does free-oligosaccharide accumulation itself cause the CDDG2 neurodevelopmental phenotype, or is it a marker of a MAN2C1 function that acts on neurodevelopment by some other route?
KNOWLEDGE GAP OPEN gap_man2c1_fos_accumulation_causality
Attached to
pathophysiology#Free oligosaccharide processing delay and accumulation pathophysiology#Neurodevelopmental malformation and cognitive phenotype
The founding cohort establishes both ends of the chain independently - accumulated and delayed free oligosaccharides in proband-derived cells, and a malformation/cognitive phenotype in the same individuals - but nothing links them. The edge between the two nodes is curated as INDIRECT_UNKNOWN_INTERMEDIATES for exactly this reason. No cell type in which accumulation is measured is a neural cell type, no dose-response between free-oligosaccharide burden and phenotype severity is reported, and no model organism has been shown to develop the malformations. The independent recovery of MAN2C1 from a polymicrogyria cohort strengthens the gene-phenotype association without touching the mechanistic link.
Proposed experiments
Free-oligosaccharide burden versus cortical phenotype in neural models
exp_man2c1_neural_fos_dose_response
Quantify free-oligosaccharide species in MAN2C1-null human iPSC-derived neural progenitors and cortical organoids across an allelic series spanning the reported hypomorphic and null variants, and test whether burden tracks with migration and lamination defects. A rescue arm restoring cytosolic alpha-mannosidase activity without restoring MAN2C1 protein would separate the catabolic function from any moonlighting role.
Cortical phenotyping of a Man2c1-deficient model organism
exp_man2c1_model_organism_cortical_phenotype
Determine whether a Man2c1 loss-of-function mouse or zebrafish reproduces polymicrogyria-like cortical disorganization and callosal anomalies, and whether free-oligosaccharide accumulation precedes them developmentally. A model that accumulates free oligosaccharides without the malformation would refute the direct-causation reading.
⚙

Pathophysiology

3
MAN2C1 cytosolic alpha-mannosidase deficiency
Biallelic MAN2C1 variants reduce cytosolic alpha-mannosidase activity required for processing free oligosaccharides.
MAN2C1 hgnc:6827 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAN2C1 (hgnc:6827). hgnc:6827 is a gene from the HUGO Gene Nomenclature Committee.
oligosaccharide catabolic process GO:0009313 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oligosaccharide catabolic process (GO:0009313). GO:0009313 is a biological process from the Gene Ontology. ↓ DECREASED
alpha-mannosidase activity GO:0004559 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased alpha-mannosidase activity (GO:0004559). GO:0004559 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Free oligosaccharide processing delay and accumulation MAN2C1 deficiency delays cytosolic free oligosaccharide trimming and causes free oligosaccharide accumulation in patient cells.
Show evidence (2 references)
PMID:35045343 SUPPORT Human Clinical
"The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1"
The study identifies MAN2C1 as the cytosolic mannosidase in free oligosaccharide catabolism.
PMID:41623318 SUPPORT Human Clinical
"The MAN2C1 gene encodes an enzyme with alpha-mannosidase 2C1 activity, which is responsible for the degradation of defective glycoproteins in the cytoplasm."
An independent second report restates the cytosolic alpha-mannosidase function whose loss defines the trigger node.
Free oligosaccharide processing delay and accumulation
Accumulated free oligosaccharides disrupt glycan turnover homeostasis and are associated with abnormal neurodevelopment.
oligosaccharide catabolic process GO:0009313 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oligosaccharide catabolic process (GO:0009313). GO:0009313 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neurodevelopmental malformation and cognitive phenotype Free-oligosaccharide catabolism failure is associated with intellectual disability and structural brain anomalies.
Show evidence (1 reference)
PMID:35045343 SUPPORT In Vitro
"Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants."
Complementation experiments support pathogenicity of MAN2C1 variants in a cellular model.
Neurodevelopmental malformation and cognitive phenotype
The clinical phenotype includes intellectual disability and structural brain anomalies, including polymicrogyria and callosal abnormalities.
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and..."
The initial cohort directly describes the neurodevelopmental and congenital-anomaly phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MAN2C1-congenital disorder of deglycosylation 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"variable degrees of intellectual disability"
The cohort directly reports intellectual disability.
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35045343 SUPPORT Human Clinical
"brain anomalies including polymicrogyria"
The cohort directly reports polymicrogyria.
PMID:37486637 SUPPORT Human Clinical
"compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families"
An independent polymicrogyria cohort recovered MAN2C1 as a novel polymicrogyria gene, corroborating the phenotype from a different ascertainment route.
Callosal anomalies HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"callosal anomalies"
The cohort directly reports callosal anomalies.
🧬

Genetic Associations

1
MAN2C1 (Biallelic pathogenic variants)
Gene: MAN2C1 hgnc:6827 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAN2C1 (hgnc:6827). hgnc:6827 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:35045343 SUPPORT Human Clinical
"six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1"
The initial cohort establishes MAN2C1 as the causal gene.
PMID:41623318 SUPPORT Human Clinical
"The purpose of this report is to present a novel MAN2C1 pathogenic variant in a patient with a congenital disorder of deglycosylation 2."
The only patient reported since the founding cohort, adding a novel pathogenic allele to the MAN2C1 variant spectrum.
PMID:37486637 SUPPORT Human Clinical
"Six candidate novel polymicrogyria genes were identified or confirmed"
Independent discovery of MAN2C1 in a 275-family polymicrogyria cohort, obtained without reference to the founding CDDG2 series.
{ }

Source YAML

click to show 
name: MAN2C1-congenital disorder of deglycosylation 2
creation_date: "2026-07-06T06:04:18Z"
description: >-
  MAN2C1-congenital disorder of deglycosylation 2 is an autosomal recessive
  free-oligosaccharide catabolism disorder caused by biallelic MAN2C1 variants.
  MAN2C1 encodes a cytosolic alpha-mannosidase that trims free oligosaccharides
  generated during N-glycosylation and glycoprotein degradation. Pathogenic
  variants cause accumulation and delayed processing of free oligosaccharides in
  patient-derived cells, producing a neurodevelopmental disorder with
  dysmorphic features, congenital anomalies including tongue hamartoma,
  intellectual disability, and brain anomalies such as polymicrogyria,
  interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and
  hypoplasia of the brainstem and cerebellar vermis.
category: Mendelian
disease_term:
  preferred_term: congenital disorder of deglycosylation 2
  term:
    id: MONDO:0030770
    label: congenital disorder of deglycosylation 2
synonyms:
- CDDG2
- MAN2C1 deficiency
parents:
- congenital disorder of deglycosylation
classifications:
  icimd_category:
  - classification_value: other_glycan_metabolism
    notes: >-
      The local ICIMD enum folds the specific deglycosylation subgroup into the
      broader other_glycan_metabolism value.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported individuals have biallelic pathogenic MAN2C1 variants.
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      six individuals, including two fetuses, with bi-allelic pathogenic variants
      in MAN2C1
    explanation: >-
      The initial cohort establishes biallelic MAN2C1 variants in affected
      individuals.
pathophysiology:
- name: MAN2C1 cytosolic alpha-mannosidase deficiency
  conforms_to: "cytosolic_deglycosylation#Cytosolic Deglycosylation Enzyme Deficiency"
  description: >-
    Biallelic MAN2C1 variants reduce cytosolic alpha-mannosidase activity
    required for processing free oligosaccharides.
  role: trigger
  genes:
  - preferred_term: MAN2C1
    term:
      id: hgnc:6827
      label: MAN2C1
  molecular_functions:
  - preferred_term: alpha-mannosidase activity
    modifier: DECREASED
    term:
      id: GO:0004559
      label: alpha-mannosidase activity
  biological_processes:
  - preferred_term: oligosaccharide catabolic process
    modifier: DECREASED
    term:
      id: GO:0009313
      label: oligosaccharide catabolic process
  chemical_entities:
  - preferred_term: free oligosaccharide
    modifier: INCREASED
    term:
      id: CHEBI:50699
      label: oligosaccharide
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The catabolism of fOSs has been linked to the activity of a specific
      cytosolic mannosidase, MAN2C1
    explanation: >-
      The study identifies MAN2C1 as the cytosolic mannosidase in free
      oligosaccharide catabolism.
  - reference: PMID:41623318
    reference_title: "Congenital disorder of deglycosylation 2. Report of a novel MAN2C1 pathogenic variant and additional phenotypic implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MAN2C1 gene encodes an enzyme with alpha-mannosidase 2C1 activity,
      which is responsible for the degradation of defective glycoproteins in
      the cytoplasm.
    explanation: >-
      An independent second report restates the cytosolic alpha-mannosidase
      function whose loss defines the trigger node.
  downstream:
  - target: Free oligosaccharide processing delay and accumulation
    description: >-
      MAN2C1 deficiency delays cytosolic free oligosaccharide trimming and causes
      free oligosaccharide accumulation in patient cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35045343
      reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        MAN2C1 variants lead to accumulation and delay in the processing of fOSs
        in proband-derived cells.
      explanation: >-
        Patient-cell experiments directly support the accumulated free
        oligosaccharide node.
- name: Free oligosaccharide processing delay and accumulation
  conforms_to: "cytosolic_deglycosylation#Cytosolic Glycan Catabolite Dysregulation"
  description: >-
    Accumulated free oligosaccharides disrupt glycan turnover homeostasis and
    are associated with abnormal neurodevelopment.
  role: central_effector
  biological_processes:
  - preferred_term: oligosaccharide catabolic process
    modifier: DECREASED
    term:
      id: GO:0009313
      label: oligosaccharide catabolic process
  chemical_entities:
  - preferred_term: free oligosaccharide
    modifier: INCREASED
    term:
      id: CHEBI:50699
      label: oligosaccharide
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the
      pathogenicity of three of the identified MAN2C1 variants.
    explanation: >-
      Complementation experiments support pathogenicity of MAN2C1 variants in a
      cellular model.
  downstream:
  - target: Neurodevelopmental malformation and cognitive phenotype
    description: >-
      Free-oligosaccharide catabolism failure is associated with intellectual
      disability and structural brain anomalies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neurodevelopmental malformation and cognitive phenotype
  conforms_to: "cytosolic_deglycosylation#Neurodevelopmental and Multisystem Dysfunction"
  description: >-
    The clinical phenotype includes intellectual disability and structural brain
    anomalies, including polymicrogyria and callosal abnormalities.
  role: consequence
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals exhibit dysmorphic facial features, congenital anomalies
      such as tongue hamartoma, variable degrees of intellectual disability, and
      brain anomalies including polymicrogyria, interhemispheric cysts,
      hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem
      and cerebellar vermis.
    explanation: >-
      The initial cohort directly describes the neurodevelopmental and
      congenital-anomaly phenotype.
phenotypes:
- name: Intellectual disability
  description: Intellectual disability is reported with variable severity.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variable degrees of intellectual disability
    explanation: The cohort directly reports intellectual disability.
- name: Polymicrogyria
  description: Polymicrogyria is among the reported brain anomalies.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain anomalies including polymicrogyria
    explanation: The cohort directly reports polymicrogyria.
  - reference: PMID:37486637
    reference_title: "Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with
      consistent genotype-phenotype relationships in multiple families
    explanation: >-
      An independent polymicrogyria cohort recovered MAN2C1 as a novel
      polymicrogyria gene, corroborating the phenotype from a different
      ascertainment route.
- name: Callosal anomalies
  description: Corpus callosum anomalies are reported among structural brain findings.
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      callosal anomalies
    explanation: The cohort directly reports callosal anomalies.
genetic:
- name: MAN2C1
  association: Biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: MAN2C1
    term:
      id: hgnc:6827
      label: MAN2C1
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      six individuals, including two fetuses, with bi-allelic pathogenic variants
      in MAN2C1
    explanation: The initial cohort establishes MAN2C1 as the causal gene.
  - reference: PMID:41623318
    reference_title: "Congenital disorder of deglycosylation 2. Report of a novel MAN2C1 pathogenic variant and additional phenotypic implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this report is to present a novel MAN2C1 pathogenic
      variant in a patient with a congenital disorder of deglycosylation 2.
    explanation: >-
      The only patient reported since the founding cohort, adding a novel
      pathogenic allele to the MAN2C1 variant spectrum.
  - reference: PMID:37486637
    reference_title: "Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six candidate novel polymicrogyria genes were identified or confirmed
    explanation: >-
      Independent discovery of MAN2C1 in a 275-family polymicrogyria cohort,
      obtained without reference to the founding CDDG2 series.
discussions:
- discussion_id: gap_man2c1_fos_accumulation_causality
  prompt: >-
    Does free-oligosaccharide accumulation itself cause the CDDG2
    neurodevelopmental phenotype, or is it a marker of a MAN2C1 function that
    acts on neurodevelopment by some other route?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Free oligosaccharide processing delay and accumulation
  - pathophysiology#Neurodevelopmental malformation and cognitive phenotype
  rationale: >-
    The founding cohort establishes both ends of the chain independently -
    accumulated and delayed free oligosaccharides in proband-derived cells, and
    a malformation/cognitive phenotype in the same individuals - but nothing
    links them. The edge between the two nodes is curated as
    INDIRECT_UNKNOWN_INTERMEDIATES for exactly this reason. No cell type in
    which accumulation is measured is a neural cell type, no dose-response
    between free-oligosaccharide burden and phenotype severity is reported, and
    no model organism has been shown to develop the malformations. The
    independent recovery of MAN2C1 from a polymicrogyria cohort strengthens the
    gene-phenotype association without touching the mechanistic link.
  proposed_experiments:
  - experiment_id: exp_man2c1_neural_fos_dose_response
    name: Free-oligosaccharide burden versus cortical phenotype in neural models
    description: >-
      Quantify free-oligosaccharide species in MAN2C1-null human iPSC-derived
      neural progenitors and cortical organoids across an allelic series
      spanning the reported hypomorphic and null variants, and test whether
      burden tracks with migration and lamination defects. A rescue arm
      restoring cytosolic alpha-mannosidase activity without restoring MAN2C1
      protein would separate the catabolic function from any moonlighting role.
  - experiment_id: exp_man2c1_model_organism_cortical_phenotype
    name: Cortical phenotyping of a Man2c1-deficient model organism
    description: >-
      Determine whether a Man2c1 loss-of-function mouse or zebrafish
      reproduces polymicrogyria-like cortical disorganization and callosal
      anomalies, and whether free-oligosaccharide accumulation precedes them
      developmentally. A model that accumulates free oligosaccharides without
      the malformation would refute the direct-causation reading.
notes: >-
  Only two publications describe MAN2C1-related disease directly. The 2026
  second report (PMID:41623318) is a compound case: the pathogenic MAN2C1
  variant sits opposite a 15q24.1q24.3 microdeletion that itself removes
  MAN2C1, so the CDDG2 features are unmasked on the deleted background rather
  than arising from two conventional point alleles. Its phenotype should not be
  attributed wholly to MAN2C1 - the microdeletion spans other genes, and the
  authors present the case as clarifying which 15q24-deletion features are
  MAN2C1-attributable. MAN2C1 was independently recovered as a novel
  polymicrogyria gene in a 275-family exome cohort (PMID:37486637), which is
  the strongest corroboration of the gene-phenotype link that exists outside
  the founding series.